Introduction

Active tuberculosis may develop soon after the initiation of treatment with infliximab, a humanized murine monoclonal antibody against tumor necrosis factor (TNF) α. Of the patients with infliximab-associated tuberculosis 56% have extrapulmonary symptoms, and 24% have disseminated disease [1]. Accumulating evidence suggests that TNF-α also plays a crucial role in the response to fungal pathogens, including Aspergillus fumigatus [2]. Since the worldwide approval of infliximab for rheumatoid arthritis and Crohn’s disease an increasing number of fungal infections have been reported, including disseminated coccidioidomycosis, cryptococcosis, histoplasmosis, Pneumocystis carinii pneumonia, pulmonary aspergillosis, and systemic Candida infections [1, 3]. Recently infliximab has been associated with the reactivation of viral infections such as varicella zoster virus, molluscum contagiosum, and cytomegalovirus [4, 5, 6]. We present the case of a patient who developed three opportunistic infections during therapy with infliximab and methotrexate, requiring prolonged mechanical ventilation and intensive care treatment.

Case report

A 58-year-old Creole woman was admitted to the intensive care unit of another hospital because of somnolence, severe hyponatremia (101 mmol/l), fever, bilateral pulmonary infiltrates, and respiratory failure. Her medical history included mild rheumatoid arthritis for which she received infliximab (10 mg/kg, every 2 months) and methotrexate (7.5 mg/week) in a clinical trial for 14 months. Since she had a positive (13 mm) tuberculin skin test before the start of therapy without signs or symptoms of active tuberculosis, she received isoniazid (INH) for 6 months (300 mg daily). Initial Gram staining and culture of the sputum yielded growth of Haemophilus influenzae, Escherichia coli, and Citrobacter freundii. After initial improvement she developed respiratory failure and needed ventilatory support and was transferred to our unit.

On admission she was comatose with a right-sided hemiparesis; there was disseminated intravascular coagulation, pancytopenia, and shock. Because an additional opportunistic pulmonary infection was suspected, bronchoalveolar lavage (BAL) was performed. Ziehl-Neelsen staining was positive (+5). Thrombocytopenia and disseminated intravascular coagulation prohibited lumbal puncture. Treatment consisted of intravenous volume expansion, inotropic support, mechanical ventilation, selective decontamination of the digestive tract, cefotaxim, ciproxin, enteral immunonutrition (Impact), antituberculous drugs (ethambutol, INH, pyrazinamide and rifampicin), and corticosteroids [7, 8]. Since the patient had persistent high fever and developed progressive pulmonary infiltrates and multiple ulcerations on the lower abdomen and genitals, a second BAL was performed on day 17, which showed growth of A. fumigatus. Herpes simplex virus type 2 was cultured from the abdominal and genital ulcerations but not from the BAL specimens. Skin biopsy findings supported the diagnosis of genital herpes. Further treatment consisted of amphotericin B, flucytosine, and later valaciclovir.

On admission, leukocytopenia was noted (3.1×109/l, 78% neutrophil granulocytes) with the following deficiencies: CD4+ count: 0.25×109/l (0.56–1.55); CD4+%: 49 (35–74); CD8+ count: 0.15×109/l (0.31–1.0); CD8+%: 30 (17–52); CD4+/CD8+ ratio: 1.63 (0.81–3.0). Analysis included bone marrow aspiration and culture. Test for human immunodeficiency virus antibodies was negative. Ziehl-Neelsen staining of the sputum remained positive for 5 weeks. The Mycobacterium tuberculosis, which was cultured from BAL fluid and bone marrow, was sensitive to the administered antituberculous drugs. The concentrations of amphotericin B, flucytosine, and antituberculous drugs were within the therapeutic range. The neurological state improved very slowly. In addition to the hemiparesis, there was severe critical illness polyneuropathy. She was discharged after 63 days of intensive care treatment and 54 days of mechanical ventilation. Her score on the Acute Physiology and Chronic Health Evaluation II was 31 (predicted mortality 0.73).

Several weeks later she was transferred to a rehabilitation center. However, after 1 week she was readmitted because of dyspnea and arthritis. After 4 months of treatment with antituberculous drugs M. tuberculosis was cultured from a metacarpal-phalangeal joint of the right hand.

Discussion

A variety of cytokine-based strategies are being explored for the treatment of chronic inflammatory diseases such as Crohn’s disease and rheumatoid arthritis and more recently for sepsis [9]. Given the complexity of cytokine interactions and the multiplicity of cytokine targets the effectiveness and toxicity of cytokine-based interventions are difficult to predict. Disseminated infections may arise, especially the reactivation of latent tuberculosis and herpes viruses, and the development of fungal infections. This risk is greatly increased in patients with concurrent immunosuppression, such as corticosteroids, azathioprine, methotrexate, and mercaptopurine [1, 3].

The present case is important for several reasons. First, the finding of a community acquired bacterial pneumonia with common pathogens does not exclude the coexistence of tuberculosis. Secondly, the treatment of latent tuberculosis (formerly called “chemoprophylaxis”) with a 6-month INH regimen does not always protect against the reactivation and dissemination of tuberculosis [10]. It has been demonstrated that among patients who take more than 80% of the prescribed doses the 6-month regimen decreases the incidence of active tuberculosis by 69% and the 12-month regimen by 93% compared with the 3-month regimen [11]. Therefore INH alone is not the gold standard for prophylaxis in high-risk patients. In retrospect, our patient had taken more than 80% of the prescribed dose, according to data from the referring hospital.

Thirdly, combination therapy with infliximab and methotrexate may cause a severe form of immunosuppression with multiple opportunistic infections due to prolonged leukocytopenia and depressed cellular immunity. The global reduction in CD4+ and CD8+ T-lymphocytes that we observed in our patient has been reported before [5, 12]. On the other hand, prolonged critical illness itself, especially disseminated tuberculosis, may cause pancytopenia and CD4+ T-lymphocytopenia, thereby creating additional immunosuppression which may further contribute to the development of other (fungal) infections [13, 14]. Since granulocytopenia was not observed (defined as a neutrophil count of <500×109/l), treatment with granulocyte or granulocyte-macrophage colony-stimulating factor was not instituted.

Finally, since there is currently no specific immune-enhancing therapy available, treatment of these patients should consist of general supportive measures, organ replacement therapy, appropriate anti-microbial therapy, early enteral immunonutrition, and infection prevention with selective decontamination of the digestive tract to avoid Gram-negative ventilator associated pneumonia [15]. After withdrawal of infliximab the immunodepressant effects persist for many months [1]. Therefore antituberculous therapy should probably be continued as long as the immunodepressant effects last [16]. In the absence of prospective data resumption of infliximab therapy is not recommended. Both physicians and patients should be aware of these side effects.

Conclusion

Combination therapy with infliximab and methotrexate may cause various opportunistic infections. In addition to supportive measures and specific antimicrobial therapy early enteral immunonutrition and other infection preventive measures may be of crucial importance in the treatment of these patients. Therapy with four first-line antituberculous drugs (INH, rifampicin, pyrazinamide, and ethambutol) may be needed for more than 8 weeks because of severe and prolonged immunosuppression.